Biology subjects

Sundaresan, A.

Publications and source records attributed to Sundaresan, A..

6 recordsLinked to original sources

bioRxiv2026

Milankovic cycles and Cultural Evolution as Important Catalysts for Hominin Genetic Diversification

Climate variability is widely considered a key driver of human evolution, yet the mechanisms linking long-term climate change driven by Milankovi[c] cycles to hominin demography and genetic diversity remain elusive. Here we couple an agent-based demographic model, incorporating an idealized genetic marker, cultural dynamics, and a realistic Pleistocene climate framework, to quantify how astronomically forced climate and vegetation variability shaped the genetic structure of African hominins over the past 1.9 Myr. We show that warm early Pleistocene climates sustained a continent-wide network of genetically diverse demes until ~900 ka. The subsequent decline in atmospheric CO2, associated cooling, and reduced vegetation during the Mid-Pleistocene Transition triggered widespread demographic collapse, with populations surviving only in southern and eastern Africa. This reorganization in population structure leads to a decline in simulated genetic diversity, consistent in timing with genomic and archeological evidence. Introducing cultural innovations in the model, represented as enhanced carrying capacity, enables hominin populations to recover from this diversity bottleneck, adapt to increasingly harsh late Pleistocene environments and long glacial periods, rapidly expand across Africa during interglacials, and ultimately disperse into Eurasia. Our results identify Milankovi[c]-scale climate forcing and cultural growth as important catalysts of hominin population structure and genetic diversification.

evolutionary biology↗

bioRxiv2025

B cell transcriptomics reveals lasting dysregulation and rapid decline of protective memory after hepatitis C cure

O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/664545v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@d12426org.highwire.dtl.DTLVardef@9c54daorg.highwire.dtl.DTLVardef@186d559org.highwire.dtl.DTLVardef@120f2f3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG HighlightsO_LIB cells in CHC patients retained dysregulated transcriptional profiles despite successful DAA treatment C_LIO_LIB cell dysregulation is marked by global B cell hyperactivation and antigen-specific atypical MBC expansion C_LIO_LISustained upregulation of TNF- signaling via NF-{kappa}B (TNF-/NF-{kappa}B) is a central driver of persistent B cell dysregulation and chronic inflammation C_LIO_LIViral clearance leads to restoration of IFN responses and IFN-stimulated gene (ISG) signatures in B cells but not TNF-/NF-{kappa}B C_LIO_LIHCV IGHV1-69 bnAb-producing B cells are enriched within the CD86hi IgG MBC subset before treatment C_LIO_LICD86hi IgG MBC subset contracts rapidly post-cure in parallel with the rapid decline of cross-nAb responses and loss of protective immune memory against HCV reinfection C_LI Chronic hepatitis C (CHC) disrupts host humoral immune response by impairing the timely generation of neutralizing antibody (nAb) and durable immune memory. However, the underlying mechanisms and their reversibility after viral clearance remain poorly defined. Here, through integrated single-cell transcriptomics and antibody repertoire characterization, we show that B cells from CHC patients retain transcriptional dysregulation even after successful antiviral therapy. Sustained TNF- signaling emerged as a central driver of chronic B cell hyperactivation, persistent dysregulation and unresolved inflammation following cure. Furthermore, a CD86hi memory B cell subset, responsible for an IGHV1-69-encoded multi-donor class recall nAb response, declined rapidly following viral clearance, compromising immune memory against reinfection. Together, these findings reveal how CHC imprints lasting B cell dysregulation, impairs nAb memory, and sustains inflammation in the B cell compartment, after viral clearance. The insights underscore the need for strategies aimed at restoring B cell homeostasis to achieve durable immune protection.

immunology↗

bioRxiv2025

X-Linked Cancer-Associated Polypeptide (XCP) from lncRNA1456 Cooperates with PHF8 to Regulate Gene Expression and Cellular Pathways in Breast Cancer

Recent studies have demonstrated that a subset of long "noncoding" RNAs (lncRNAs) produce functional polypeptides and proteins. In this study, we discovered a 132 amino acid protein in human breast cancer cells named XCP (X-linked Cancer-associated Polypeptide), which is encoded by lncRNA1456 (a.k.a. RHOXF1P3), a transcript previously thought to be noncoding. lncRNA1456 is a pancreas- and testis-specific RNA whose gene is located on chromosome X. We found that the expression of lncRNA1456 and XCP are highly upregulated in the luminal A, luminal B, and HER2 molecular subtypes of breast cancer. XCP modulates both estrogen-dependent and estrogen-independent growth of breast cancer cells by regulating cancer pathways, as shown in cell and xenograft models. XCP shares some homology with homeodomain-containing proteins and interacts with the histone demethylase plant homeodomain finger protein 8 (PHF8), which is also encoded by an X-linked gene. Mechanistically, XCP stimulates the histone demethylase activity of PHF8 to regulate gene expression in breast cancer cells. These findings identify XCP as a coregulator of transcription and emphasize the need to interrogate the potential functional roles of open reading frames originating from noncoding RNAs. Statement of SignificangeXCP, a polypeptide encoded by an X-linked lncRNA, regulates gene expression in breast cancer cells. XCP is a chromatin-associated protein that interacts with the histone demethylase PHF8 and modulates its demethylase activity to regulate gene expression. XCP drives cancer-specific phenotypes and serves as a potential biomarker and/or target for therapeutic intervention.

cancer biology↗

bioRxiv2024

Deep Profiling of Plasma Proteoforms with Engineered Nanoparticles for Top-down Proteomics

The dynamic range challenge for detection of proteins and their proteoforms in human plasma has been well documented. Here, we use the nanoparticle protein corona approach to enrich low-abundant proteins selectively and reproducibly from human plasma and use top-down proteomics to quantify differential enrichment for the 2841 detected proteoforms from 114 proteins. Furthermore, nanoparticle enrichment allowed top-down detection of proteoforms between [~]1 {micro}g/mL and [~]10 pg/mL in absolute abundance, providing up to 105-fold increase in proteome depth over neat plasma in which only proteoforms from abundant proteins (>1 {micro}g/mL) were detected. The ability to monitor medium and some low abundant proteoforms through reproducible enrichment significantly extends the applicability of proteoform research by adding depth beyond albumin, immunoglobins and apolipoproteins to uncover many involved in immunity and cell signaling. As proteoforms carry unique information content relative to peptides, this report opens the door to deeper proteoform sequencing in clinical proteomics of disease or aging cohorts.

biochemistry↗

bioRxiv2021

ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

ATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with the MCM replication complex and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.

molecular biology↗

bioRxiv2019

Differential contribution of p300 and CBP to regulatory elements in mESCs

The transcription coactivators CREB binding protein (CBP) and p300 are highly homologous acetyltransferases that mediate histone 3 lysine 27 acetylation (H3K27ac) at regulatory elements such as enhancers and promoters. Although in most cases, CBP and p300 are considered to be functionally identical, both proteins are indispensable for development and there is evidence of tissue-specific nonredundancy. However, characterization of chromatin and transcription states regulated by each protein is lacking. In this study we analyze the individual contribution of p300 and CBP to the H3K27ac landscape, chromatin accessibility, and transcription in mouse embryonic stem cells (mESC). We demonstrate that p300 is responsible for the majority of H3K27ac in mESCs and that loss of acetylation in p300-depleted mESCs is more pronounced at enhancers compared to promoters. While loss of either CBP or p300 has little effect on the open state of chromatin, we observe that distinct gene sets are transcriptionally dysregulated upon depletion of p300 or CBP. Transcriptional dysregulation is generally correlated with dysregulation of promoter acetylation upon depletion of p300 (but not CBP) and appears to be relatively independent of dysregulated enhancer acetylation. Interestingly, both our transcriptional and genomic analyses demonstrate that targets of the p53 pathway are stabilized upon deletion of p300, suggesting that this pathway is highly prioritized when p300 levels are limited.

genomics↗